Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature

doi:10.3969/j.issn.1006-7795.2018.06.025

Journal of Capital Medical University ›› 2018, Vol. 39 ›› Issue (6): 937-944.doi: 10.3969/j.issn.1006-7795.2018.06.025

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Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature

Hu Xuyun¹, Wu Di², Li Mengting³, Chen Jiajia², Li Xiaoqiao², Su Chang², Chen Shaoke³, Shen Yiping^3,4,5, Gong Chunxiu²

1. Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, Center for Medical Genetics, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
2. Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
3. Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning 530003, China;
4. Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China;
5. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston 02115, USA

Received:2018-10-22 Online:2018-11-21 Published:2018-12-19
Supported by:
This study was supported by National Natural Science Foundation of China (81570220).

Abstract

Abstract: Objective To evaluate the clinical phenotypes and genetic variations of three Chinese patients with familial short stature and brachydactyly. Methods Three patients with short stature and brachydactyly from Beijing Children's Hospital were molecularly confirmed with specific subtypes of brachydactyly via next generation sequencing. Their parents were also sequenced for segregation information. Growth hormone therapy was initiated after diagnosis. Results c.283_285delGAG/p.E95del in IHH, c.2625dupC/p.T876fs*20 in ROR2 or c.413delA/p.K138fs*11 in PTHLH was identified in every family, thus the patients from these three families were diagnosed as brachydactyly A1, brachydactyly B1 and brachydactyly E2, respectively. After growth hormone therapy, the heights of three patients were significantly improved (+0.99 SD,+0.64 SD and+2.69 SD respectively). Conclusion The genetic heterogeneity of brachydactyly combined with short stature can be uncovered by next generation sequencing. In this study, we reported two novel pathogenic variants in ROR2 and PTHLH genes, as well a previously reported IHH hotspot mutation which was identified in Chinese population for the first time. Growth hormone therapy was effective for all three patients.

Key words: short, stature brachydactyly, genetic diagnosis, next generation sequencing, growth hormone therapy

CLC Number:

R725

Hu Xuyun, Wu Di, Li Mengting, Chen Jiajia, Li Xiaoqiao, Su Chang, Chen Shaoke, Shen Yiping, Gong Chunxiu. Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature[J]. Journal of Capital Medical University, 2018, 39(6): 937-944.

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References

[1] Mundlos S. The brachydactylies:a molecular disease family[J]. Clin Genet, 2009, 76(2):123-136.
[2] Temtamy S A, Aglan M S. Brachydactyly[J]. Orphanet J Rare Dis, 2008, 3:15.
[3] Lodder E M, Hoogeboom A J, Coert J H, et al. Deletion of 1 amino acid in Indian hedgehog leads to brachydactylyA1[J]. Am J Med Genet A, 2008, 146A(16):2152-2154.
[4] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[5] Ma G, Yu J, Xiao Y, et al. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels[J]. Cell Res, 2011, 21(9):1343-1357.
[6] Gao B, Guo J, She C, et al. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1[J]. Nat Genet, 2001, 28(4):386-388.
[7] Kirkpatrick T J, Au K S, Mastrobattista J M, et al. Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus[J]. J Med Genet, 2003, 40(1):42-44.
[8] Liu Y, Ross J F, Bodine P V, et al. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation[J]. Mol Endocrinol, 2007, 21(12):3050-3061.
[9] Oldridge M, Fortuna A M, Maringa M, et al. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B[J]. Nat Genet, 2000, 24(4):275-278.
[10] Schwabe G C, Tinschert S, Buschow C, et al. Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B[J]. Am J Hum Genet, 2000, 67(4):822-831.
[11] Hamamy H, Saleh N, Oldridge M, et al. Brachydactyly type B1:report of a family with de novo ROR2 mutation[J]. Clin Genet, 2006, 70(6):538-540.
[12] Dong S, Wang Y, Tao S, et al. Mutation screening in candidate genes in four Chinese brachydactyly families[J]. Ann Clin Lab Sci, 2015, 45(1):94-99.
[13] Hiremath M, Wysolmerski J. Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development[J]. J Mammary Gland Biol Neoplasia, 2013, 18(2):171-177.
[14] Klopocki E, Hennig B P, Dathe K, et al. Deletion and point mutations of PTHLH cause brachydactyly type E[J]. Am J Hum Genet, 2010, 86(3):434-439.
[15] Pereda A, Garzon-Lorenzo L, Garin I, et al. The p.R56*mutation in PTHLH causes variable brachydactyly type E[J]. Am J Med Genet A, 2017, 173(3):816-819.
[16] Thomas-Teinturier C, Pereda A, Garin I, et al. Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review[J]. Am J Med Genet A, 2016, 170(3):734-742.
[17] Jamsheer A, Sowinska-Seidler A, Olech E M, et al. Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene[J]. J Hum Genet, 2016, 61(5):457-461.
[18] Page M M, Hooper A J, Glendenning P, et al. Isolated brachydactyly type E and idiopathic pancreatitis in a patient presenting to a lipid disorders clinic[J]. BMJ Case Rep, 2017, 2017:pii.
[19] Vasques G A, Funari M F A, Ferreira F M, et al. IHH gene mutations causing short stature with nonspecific skeletal abnormalities and response to growth hormone therapy[J]. J Clin Endocrinol Metab, 2018, 103(2):604-614.

Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature

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